Rest and Digest-The Basal Role of Autophagy in Neurons and Its Relevance to Parkinson's Disease.
Rest and Digest-The Basal Role of Autophagy in Neurons and Its Relevance to Parkinson's Disease.
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DOI：
10.1002/mds.29165
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发表时间：
2022-09
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影响因子：
--
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中科院分区：
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自噬功能障碍、线粒体损伤和神经炎症都与帕金森病（PD）有关。然而，对于自噬在健康神经元中的基本作用及其作为稳态控制的一部分对线粒体来源炎症的调节，人们知之甚少。在“脑源性自噬体分析揭示了神经元基底自噬吞噬富含核的线粒体片段”中，Goldsmith等人提供了有趣的证据，表明基底自噬调节突触维持、生物能量需求和炎症之间的平衡。在此过程中，他们揭示了自噬在突触和线粒体稳态中的关键作用，以及神经变性的可能线索。在他们的研究中，Goldsmith及其同事富集了小鼠大脑中的自噬囊泡（AVs），并通过蛋白质组学鉴定了它们的货物，根据AV分数分配货物分数，以确定其是否被自噬体降解。这种新方法在AVs中鉴定出4,190种独特的蛋白质，其中突触和线粒体蛋白质含量最高，从而为基础条件下大脑中主要的自噬货物提供了新的见解。有趣的是，AVs缺乏PINK1、Parkin或选择性线粒体自噬受体，但TBK1（一种ikk激酶和与自噬货物招募相关的先天免疫蛋白）富集。这一新信息表明，线粒体片段的基底自噬体吞噬没有损伤，反而可能有助于线粒体和免疫稳态。
Autophagic dysfunction, mitochondrial damage, and neuroinflammation are all implicated in Parkinson’s disease (PD) 1; however, much less is understood about the basal role of autophagy in healthy neurons and its regulation of mitochondrial derived inflammation as part of homeostatic control. In “Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons,” Goldsmith et al. provide intriguing evidence that basal autophagy regulates a balance between synaptic maintenance, bioenergetic demands, and inflammation. In doing so, they uncover a key role for autophagy in synaptic and mitochondrial homeostasis, and possible clues for neurodegeneration.In their study, Goldsmith and colleagues enriched autophagic vesicles (AVs) from the mouse brain and identified their cargo via proteomics, assigning a cargo score based on the AV fraction to determine if it was destined for autophagosomal degradation. This novel approach yielded 4,190 unique proteins identified within AVs, of which synaptic and mitochondrial proteins were most enriched, thus providing new insight into the predominant autophagic cargo in the brain under basal conditions. Interestingly, AVs lacked PINK1, Parkin, or selective mitochondrial autophagy receptors, however TBK1, an IKK-kinase and innate immunity protein associated with autophagic cargo recruitment, was enriched. This new information suggests basal autophagosomal engulfment of mitochondrial fragments occurs without damage, instead potentially contributing to mitochondrial and immune homeostasis.
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